Substituted 1h-pyrido(2,3-b)(1,4)thiazine-2(3h)-thiones

ABSTRACT

NOVEL SUBSTITUTED 1H - PYRIDO(2,3-B)(1,4)THIAZINES-2 (3H)-THIONES REPRESENTED BY THE FORMULA   2-(S=),3-R,X-2,3-DIHYDRO-1H-PYRIDO(2,3-B)(1,4)THIAZINE   WHEREIN X IS HYDROGEN, HYDROXY, MERCAPTO, LOWER ALKYL, LOWER ALKOXY OR HALO AND R IS HYDROGEN, HYDROXY, LOWER ALKYL, LOWER ALKOXY ORHALO. THE COMPOUNDS EXHIBIT ANTIINFLAMMATORY AND ANTI-SECRETORY ACTIVITY.

3,728,343 SUBSTITUTED lH-PYRIDO[2,3-b][1,4]THIAZINE- 2(3H)-THIONES Kao Hwang, Highland Park, and James Daniel Ratajczyk, waukgglan, 111., assignors to Abbott Laboratories, Chicago, l No Drawing. Filed Oct. 4, 1971, Ser. No. 186,502 Int. Cl. C0711 99/10 U.S. Cl. 260-443 R 2 Claims ABSTRACT OF THE DISCLOSURE Novel substituted 1H-pyrido[2,3-b] [1,4]thiazines 2 (3I-I)-thiones represented by the formula wherein X is hydrogen, hydroxy, mercapto, lower alkyl, lower alkoxy or halo and R is hydrogen, hydroxy, lower alkyl, lower alkoxy or halo. The compounds exhibit antiinflammatory and anti-secretory activity.

Detailed description of the invention This invention relates to novel substituted lH-pyrido [2,3-b][1,4]thiaZine-2(3H)-thiones and to methods of treating inflammation and peptic ulcers therewith.

Peptic ulcers are classically treated through the use of antacids, anticholinergic agents and controlled diet. While the antacids provide relief, they are usually taken in dosages which do not effectively alter the pH of the gastric contents, and, since they enhance stomach emptying, their duration of action is shortened by their rapid removal from the stomach. The anticholinergics reduce gastric secretion by blocking the parasympathetic stimuli to the stomach. However, these agents also block the parasympathetic stimuli to many other organs, e.g., the eye, heart, bladder, etc. This additional blocking is often manifested by undesirable side eifects such as blurred vision, urinary retention, and the like. Thus, the search for improved agents for treating peptic ulcers continues.

One class of compounds which is useful in the treatment of peptic ulcers is the anti-secretory agents. Such compounds reduce the volume and acidity of gastric secretion through mechanisms other than the blockade of the cholinergic system. The present invention provides such compounds.

The com-pounds of this invention are represented by the formula H N s lr X- wherein X is hydrogen, hydroxy, mercapto, lower alkyl, lower alkoxy or halo and R is hydrogen, hyroxy, loweralkoxy, lower alkoxy or halo.

The term lower alkyl as used herein refers to both straight and branched chain C -C alkyls including methyl, ethyl, N-propyl, iso-propyl, N-butyl, sec-butyl, tert-butyl, N-pentyl, iso-pentyl, neo-pentyl, N-hexyl and the like.

The term lower alkoxy refers to C -C alkoxy groups, including methoxy, ethoxy and propoxy.

The term halo includes chloro, fiuoro, bromo and iodo.

Representative compounds include:

1H-pyrido[2,3-b] [l,4]thiazine-2(3H)-thione 6- or 7 or 8- chloro-1H-pyrido[2,3-b] [1,4] -thiazine-2(3H) -thione United States Patent Ofiice 3,728,343 Patented Apr. 17, 1973 6- or 7- or 8-hydroxy-1H-pyrido[2,3-b][1,4]-thiazine 2 (3H)-thione 6- or 7- or S-methyl-lH-pyrido[2,3-b][1,4]-thiazine 2 (3H)-thione 3,6- or 7,8-dimethyl-1H-pyrido[2,3 b][1,4]thiazine 2 (3H)-thione 3-n-propyl-lH-pyrido [2,3-b] [1,4] thiazine-2 (3H) -thione 6- or 7- or 8-methoxy-1H-pyrid0[2,3-b] [1,4]-thiazine 2 (3H)-thione The compounds of this invention exhibit anti-secretory activity in test animals and are useful in treating peptic ulcers by reducing the rate of gastric secretion when administered to ulcer patients in dosages of 1-10 mg/kg. of body weight daily. The anti-secretory activity of the compounds was established using the modified pylorusligated rat technique. [Shay et al., Gastroenterology, 26, 906 (1954) and Meyer et al., J. Med. Chem, 8, 515 (1965).] The presently preferred compound is lH-pyrido [2,3-b] [1,4]thiazine-2(3H)-thione. The compound has an ED of approximately 1.2 mg./kg. and is unexpectedly five times as potent as the corresponding oxygen-containing compound, 2,3-dihydro-1H-pyrido[2,3-b] [1,4] thiazine-2-one.

In addition to the anti-secretory activity, the compounds of this invention exhibit anti-inflammatory activity at dosages off rom 10 to 100 rug/kg. The anti-inflammatory activity was established in the carrageenin rat paw edema test [Winter et al., Proc. Soc. Exp. Biol. Med, 111, 544 (1962)]. The compounds are generally administered in single or divided doses over a period of 24 hours to provide symptomatic relief of inflammation and its concomitant pain, swelling, tenderness, etc.

Generally speaking, the compounds (II) of this invention are prepared by reacting the corresponding 2,3-dihydro-1H-pyrido[2,3-b][1,4]thiazine 2 ones (I) with P 8 in the presence of pyridine and heat. According to the following reaction sequence:

:0 S A pyridine 255 -A- X13) R N S N S (I) (II) The compounds of Formula I are prepared according to the methods disclosed in U.S. Pat. No. 3,546,220.

The following example further illustrates this invention:

EXAMPLE 1 Preparation of lH-pyrido[2,3-b] l,4]thiazine-2(3H)- thione 16.6 g. (0.1 mole) of 2,3-dihydro-1H-pyrido[2,3-b][1, 4j-thiazine-2-one and 16.6 g. (0.075 mole) of P 5 were stirred in 200 ml. of pyridine at reflux temperature overnight. The resulting dark pyridine solution was decanted from a heavier syrup and concentrated in vacuo. The residue was crystallized from hot l-butanol with filtration to yield 14.4 g. of crude product, M..P. 229-231 dec. The product sinters above 220". Recrystallization from butanol and drying in vacuo at yielded the product, M.P. -225 dec.

Analysis-Calcd. for CqH N S (percent): 46.16; H, 3.32; N, 15.37; S, 35.18. Found (percent): C, 46.24; H, 3.17; N, 13.69; S, 36.70. IR and NMR data confirmed the identity of the compound.

While the compound can be administered alone, that is, as the sole component in a filled capsule, it is preferred to formulate the compound in various dosage forms for oral administration such as tablets, syrups and the like. Such dosage forms are prepared by methods well known in the lower alkoxy or halo and R is hydrogen, hydroxy, lowerart and generally include a pharmaceutically acceptable alkyl, loweralkoxy or halo. carrier or diluent such as lactose, starch or sucrose along 2. A compound in accordance with claim 1, 1H-pyrido with lubricating agents such as magnesium stearate and [2,3-b] [1,4]thiazine-2(3H)-thione. flavoring and sweetening agents and the like. 5

We claim: References Cited 1. A compound Of the formula UNITED STATES PATENTS 3,546,220 12/1970 Stein et al. 260243 S g I JOHN M. FORD, Primary Examiner R N S US. Cl. X.R.

wherein X is hydrogen, hydroxy, mercapto, lower alkyl, 424246 

